WO2010035253A1

WO2010035253A1 - Effective nitric oxide generating preparations

Info

Publication number: WO2010035253A1
Application number: PCT/IL2008/001303
Authority: WO
Inventors: Joshua Waldhorn
Original assignee: Joshua Waldhorn
Priority date: 2008-09-28
Filing date: 2008-09-28
Publication date: 2010-04-01

Abstract

The invention discloses an orally compatible, palatable composition suitable as a Nitric Oxide (NO) in vivo enhancer. The aforementioned composition comprises an effective dosage of a soluble nitrate substrate. The main innovation is that the nitrate substrate is adapted for prolonged interaction with the saliva of the patient. Furthermore the nitrate substrate is suitable for at least partial nitrification to endothelially absorbable nitrite ions by the naturally occurring anaerobic nitrifying bacteria of the saliva.

Description

EFFECTIVE NITRIC OXIDE GENERATING PREPARATIONS

FIELD OF INVENTION

[001] The present invention deals with novel compositions, effective for the treatment and the prevention of medical disorders and ailments, especially cardiovascular disease and hypertension. More specifically, the invention pertains to a method for treating and preventing medical disorders and ailments, especially cardiovascular disease and hypertension by effectively increasing Nitric Oxide (NO) concentrations in the blood.

BACKGROUND OF THE INVENTION

[002] High blood pressure is an increasing problem in the western world, and is a major factor in strokes and heart diseases. More than 25% of the world's adult population is hypertensive, and it has been estimated that this figure will increase to 29% by 2025. In addition, hypertension causes around 50% of coronary heart disease, and approximately 75% of strokes.

There are many synthetic drugs that can reduce blood pressure; e.g. Beta blockers such as Atenolol, Propanolol and Metoprolol; Calcium Channel Blockers such as Amlopidine, Felodipine and Verapanil; or ACE Inhibitors such as Ramipril, Lisinopril and Capxopril. However the use of such drugs is accompanied in many instances by adverse side effects including damages to patients' kidneys and livers.

[003] It would be very beneficial if a new, safer, less toxic and more natural blood pressure reducing agent could be available.

[004] Diet and exercise are sometimes regarded as the front line in managing hypertension. Diet is thought to be important for two reasons: firstly because of the protective effect of antioxidants and mono-unsaturated fats on blood vessel walls and secondly, because losing weight lowers blood pressure.

[005] Previous studies have shown that a diet rich in fruits and vegetables can reduce blood pressure (BP) and prevent adverse cardiovascular events. However, the mechanisms of this effect have not been elucidated until recently. The role of Nitric oxide (NO) as an important signaling molecule that acts in many tissues to regulate a diverse range of physiological and cellular processes was discovered in recent years by several groups of researchers. While attempting to identify the agent termed Endothelium-Derived Relaxing Factor (EDRP), responsible for promoting blood vessel relaxation and regulating vascular tone, it was initially assumed that it is a protein like most other signaling molecules. The discovery that EDRF was in fact nitric oxide (NO) - a highly reactive gas - has led to an explosion of interest in this field. Nitric oxide has now been demonstrated to play a role in a variety of biological processes including neurotransmission, immune defense, the regulation of cell death (apoptosis) and cell motility and reducing blood pressure.

[006] It is well established that mammalian cells produce NO from the amino acid L-Arginine with a family of NO synthase enzymes (NOS). The mechanism of lowering blood pressure by NO can be summarized as follows: The innermost layer of cells (the endothelium) releases nitric oxide from L-Arginine, when triggered by a family of NO synthase enzymes (NOS). Nitric oxide then sends a signal to the inner smooth-muscle cells of artery walls prompting them to dilate (relax). The artery walls relax and blood pressure eases, thus increasing the blood flow in the arteries. This system is dysfunctional in many cardiovascular disorders, including hypertension.

[007] Shortage of L-Arginine or dysfunction of NOS enzymes may be responsible, in many cases, for hypertension.

[008] A fundamentally different pathway for the generation of NO was recently described, in which digested nitrate (NO₃-) and nitrite (NO₂-) anions are converted into nitric oxide .and other bioactive nitrogen oxides.

[009] It was recently reported that drinking 500ml of beetroot juice a day can significantly reduce blood pressure. Although beetroot, like many other vegetables, has antioxidants in abundance, as well as iron, boron and folic acid, the reduction in blood pressure was attributed to the beetroot's capacity to absorb and store exceptionally high levels of nitrate. This finding can have major implications for the treatment of cardiovascular disease, as nitrates are abundant in many vegetables used in our diets. The woody consistency, aroma and overly sweet taste of raw vegetable juice (beetroot or any other nitrate rich vegetable) prevent the use of its advantageous traits. Furthermore, the usual diet in modern day life is not based on consuming high amounts of vegetables or their juices.

[010] In the light of the prior art as adumbrated above, a long felt need would be met if methods and compositions were provided to treat cardiovascular disease. More specifically, an enhancement of the beneficial effects of nitrate supplied by a vegetable-rich diet could be obtained by providing a safe, "easy to handle", low cost nitrate concentrated palatable compositions. A further long felt unmet need would be fulfilled by providing a natural composition useful in reducing blood pressure and maintaining a healthy cardiovascular system.

SUMMARY OF THE INVENTION

[Oi l] It is hence one object of the invention to disclose an orally compatible, palatable composition suitable as a Nitric Oxide (NO) in vivo enhancer. The composition comprising an effective dosage of a soluble nitrate substrate adapted for prolonged interaction with the saliva of the patient. The nitrate substrate is suitable for at least partial nitrification to endothelially absorbable nitrite ions by the naturally occurring anaerobic nitrifying bacteria of the saliva.

[012] It is another object of the invention to disclose the palatable composition, wherein the composition, after reaction with the saliva, further comprises sufficient nitrite ions in a predetermined dose such that the ions are available for acidification to the nitric oxide (NO) in the stomach of the patient.

[013] It is another object of the invention to disclose the palatable composition wherein the prolonged interaction is in the range of between about 5 sec and about 300 sec.

[014] It is another object of the invention to disclose the palatable composition wherein the prolonged interaction is in the range of between about 300 sec and about 3000 sec.

[015] It is another object of the invention to disclose the palatable composition wherein the prolonged interaction is in the range of between about 3000 sec and about 6 hours.

[016] It is another object of the invention to disclose the palatable composition wherein the substrate comprises soluble nitrite ions.

[017] It is another object of the invention to disclose the palatable composition wherein the substrate comprises nitric oxide (NO).

[018] It is another object of the invention to disclose the palatable composition wherein the nitrite ions are salts or esters of the nitrite ions.

[019] It is another object of the invention to disclose the palatable composition wherein the composition is encapsulated by a polymeric enteric coating. [020] It is another object of the invention to disclose the palatable composition wherein the enteric coating is adapted for controlled release upon exposure to the oral environment.

[021] It is another object of the invention to disclose the palatable composition wherein the enteric coating imparts protection to the composition so that the composition is protected in a low pH environment of about 3 or less while capable of releasing the composition at a pH of about 5.5 or higher.

[022] It is another object of the invention to disclose the palatable composition wherein the polymeric coat is selected from the group consisting of polysaccharide derivatives, polyacrylic acid derivatives, polyoxyethylene derivatives and polyvinyl pyrrolidone derivatives.

[023] It is another object of the invention to disclose the palatable composition wherein the composition additionally comprises encapsulated anaerobic nitrifying bacteria.

[024] It is another object of the invention to disclose the palatable composition wherein the composition additionally comprises acidifying compounds adapted for conversion of the nitrite ions to nitric oxide (NO).

[025] It is another object of the invention to disclose the palatable composition wherein the nitrate substrate is derived from a natural or chemical source.

[026] It is another object of the invention to disclose the palatable composition wherein the natural source comprises a blend of freeze-dried and/or powdered raw nitrate rich vegetables selected from a group consisting of fruiting vegetables, stem vegetables, herbs, leafy vegetables, legumes, roots and tubers or a mixture thereof.

[027] It is another object of the invention to disclose the palatable composition wherein the nitrate rich vegetables are further selected from a group consisting of Pumpkin, Celery,

Fennel, Rhubarb, Basil, Parsley, Dill, Coriander, Chives, Borage, Amarinth, Beet, Belgian endive, Butterhead lettuce, Curled lettuce, Dandelion, Spinach, Lettuce, French beans, Beetroot, Turnip and White radish or any combination thereof.

[028] It is another object of the invention to disclose the palatable composition wherein the chemical source comprises nitrate salts selected from a group consisting of sodium, potassium, lithium and calcium nitrate or a mixture thereof.

[029] It is another object of the invention to disclose the palatable composition wherein the dosage is between about 0.1 mmol and about 2 mmol per kg body weight of the patient per day. [030] It is another object of the invention to disclose the palatable composition wherein the dosage is between about 2 mmol and about 100 mmol per kg body weight of the patient per day.

[031] It is another object of the invention to disclose the palatable composition wherein the dosage corresponds to the amount normally found in 150 to 250 g of the nitrate rich vegetables.

[032] It is another object of the invention to disclose the palatable composition wherein the dosage corresponds to the amount normally found in 1500 to 2500 g of the nitrate rich vegetables.

[033] It is another object of the invention to disclose the palatable composition wherein the composition is in a form selected from a group consisting of a candy, a lozenge, a powder, pellets, a chewable tablet, tablet, a chewable gum, a chocolate bar, a lyophilized wafer, an intra-oral paper wafer, a muco-adhesive film and a non-muco-adhesive film, a tooth paste or a mouth wash.

[034] It is another object of the invention to disclose the palatable composition wherein the palatable composition additionally comprises beneficial compounds selected from a group consisting of antioxidants, trace minerals, vitamins, enzymes or any combination thereof.

[035] It is another object of the invention to disclose the palatable composition wherein -the composition is useful for treating vascular disorders.

[036] It is another object of the invention to disclose the palatable composition wherein the composition provides an improvement in at least one of the parameters selected from a group consisting of decreased blood pressure, prevention of blood clots, protecting the lining of blood vessels, relaxing blood vessels, vasodilator therapy or any combination thereof.

[037] It is another object of the invention to disclose the palatable composition wherein the decreased blood pressure is characterized by an average decrease of between about 3.2 mm Hg and about 10.4 mm Hg.

[038] It is another object of the invention to disclose the palatable composition wherein the composition is useful for controlling infections, especially stomach ulcers.

[039] It is another object of the invention to disclose the palatable composition wherein the composition is further capable of augmenting the antimicrobial and/or antiseptic effects of stomach acid.

[040] It is another object of the invention to disclose a method of treating vascular disorders, the method comprises steps of; (a) obtaining an orally compatible, palatable composition suitable as a Nitric Oxide (NO) in vivo enhancer; wherein the composition comprises an effective dosage of a soluble nitrate substrate adapted for prolonged interaction with the saliva of the patient; further wherein the nitrate substrate is suitable for at least partial nitrification to endothelially absorbable nitrite ions by the naturally occurring anaerobic nitrifying bacteria of the saliva; and, (b) administering the composition to the patient according to a predetermined protocol.

[041] It is another object of the invention to disclose the aforementioned method wherein the method comprises steps of providing an improvement in at least one of the parameters selected from a group consisting of decreased blood pressure, prevention of blood clots, protecting the lining of blood vessels, relaxing blood vessels, vasodilator therapy or any combination thereof.

[042] It is another object of the invention to disclose the aforementioned method wherein the method comprises steps of characterizing the decrease in blood pressure by an average decrease of between about 3.2 mm Hg and about 10.4 mm Hg.

[043] It is another object of the invention to disclose a method of treating infections, especially stomach ulcers in a patient comprising steps of; (a) obtaining an orally compatible, palatable composition suitable as a Nitric Oxide (NO) in vivo enhancer; wherein , the composition comprises an effective dosage of a soluble nitrate substrate adapted for prolonged interaction with the saliva of the patient; and, further wherein the nitrate substrate is suitable for at least partial nitrification to endothelially absorbable nitrite ions by the . naturally . occurring anaerobic nitrifying bacteria of the saliva; and, (b) administering the composition to the patient according to a predetermined protocol.

[044] It is another object of the invention to disclose the aforementioned methods further comprising steps of augmenting the antimicrobial and/or antiseptic effects of stomach acid.

[045] It is another object of the invention to disclose the aforementioned- methods further comprising steps of obtaining the composition adapted to comprise sufficient nitrite ions, after reaction with the saliva, in a predetermined dose such that the ions are available for acidification to the nitric oxide (NO) in the stomach of the patient.

[046] It is another object of the invention to disclose the aforementioned methods further comprising steps of obtaining the nitrate substrate adapted for prolonged interaction in a time range of between about 5 sec and about 300 sec. [047] It is another object of the invention to disclose the aforementioned methods further comprising steps of obtaining the nitrate substrate adapted for prolonged interaction in a time range of between about 300 sec and about 3000 sec.

[048] It is another object of the invention to disclose the aforementioned methods further comprising steps of obtaining the nitrate substrate adapted for prolonged interaction in a time range of between about 3000 sec and about 6 hours.

[049] It is another object of the invention to disclose the aforementioned methods further comprising steps of obtaining the substrate adapted to comprise soluble nitrite ions.

[050] It is another object of the invention to disclose the aforementioned methods further comprising steps of obtaining the substrate adapted to comprise nitric oxide (NO).

[051] It is another object of the invention to disclose the aforementioned methods further comprising steps of obtaining the nitrite ions adapted to be salts or esters of the nitrite ions.

[052] It is another object of the invention to disclose the aforementioned methods further comprising steps of encapsulating the composition by a polymeric enteric coating.

[053] It is another object of the invention to disclose the aforementioned methods further comprising steps of adapting the enteric coating for controlled release in the oral cavity.

[054] It is another object of the invention to disclose the aforementioned methods further comprising steps of adapting the enteric coating to impart protection to the composition in the low pH environment of about 3 or less while capable of releasing the composition at a pH of about 5.5 or higher.

[055] It is another object of the invention to disclose the aforementioned methods further comprising steps of selecting the polymeric coat from the group consisting of polysaccharide derivatives, polyacrylic acid derivatives, polyoxyethylene derivatives and polyvinyl . pyrrolidone derivatives.

[056] It is another object of the invention to disclose the aforementioned methods further comprising steps of obtaining the composition additionally comprising encapsulated anaerobic nitrifying bacteria.

[057] It is another object of the invention to disclose the aforementioned methods further comprising steps of obtaining the composition additionally comprising acidifying compounds adapted for conversion of the nitrite ions to nitric oxide (NO). [058] It is another object of the invention to disclose the aforementioned methods further comprising steps of obtaining the nitrate substrate derived from a natural or chemical source.

[059] It is another object of the invention to disclose the aforementioned methods further comprising steps of obtaining the natural source further derived from a blend of freeze-dried and/or powdered raw nitrate rich vegetables selected from' a group consisting of fruiting vegetables, stem vegetables, herbs, leafy vegetables, legumes, roots and tubers or a mixture thereof.

[060] It is another object of the invention to disclose the aforementioned methods further comprising steps of selecting the nitrate rich vegetables from a group consisting of Pumpkin, Celery, Fennel, Rhubarb, Basil, Parsley, Dill, Coriander, Chives, Borage, Amarnth, Beet, Belgian endive, Butterhead lettuce, Curled lettuce, Dandelion, Spinach, Lettuce, French beans, Beetroot, Turnip and White radish or any combination thereof.

[061] It is another object of the invention to disclose the aforementioned methods further comprising steps of selecting the chemical source from a group of nitrate salts consisting of sodium, potassium, lithium and calcium nitrate or a mixture thereof.

[062] It is another object of the invention to disclose the aforementioned methods further comprising steps of obtaining the dosage between about 0.1 mmol and about 2 mmol per kg body weight of the patient per day.

[063] It is another object of the invention to disclose the aforementioned methods further comprising steps of obtaining the dosage between about 2 mmol and about 100 mmol per kg body weight of the patient per day.

[064] It is another object of the invention to disclose the aforementioned methods further comprising steps of adapting the dosage to correspond to the amount normally found in 150 to 250 g of the nitrate rich vegetables.

[065] It is another object of the invention to disclose the aforementioned methods further comprising steps of adapting the dosage to correspond to the amount normally found in 1500 to 2500 g of the nitrate rich vegetables.

[066] It is another object of the invention to disclose the aforementioned methods further comprising steps of obtaining the composition in the form selected from a group consisting of a candy, a lozenge, a powder, a chewable tablet, tablet, a chewable gum, a chocolate bar, a lyophilized wafer, an intra-oral paper wafer, a muco-adhesive film and a non-muco-adhesive film, a tooth paste or a mouth wash.

[067] It is another object of the invention to disclose the aforementioned methods further comprising steps obtaining the palatable composition further comprising beneficial compounds selected from a group consisting of antioxidants, trace minerals, vitamins, enzymes or any combination thereof.

[068] The following publications are incorporated within the present invention as references, namely: Effects of dietary nitrate on blood pressure in healthy volunteers; Larsen FJ, Ekblom B, Sahlin K, Lundberg JO, Weitzberg E.; N Engl J Med. 2007 Apr 12; 356(15):1590; Effects of dietary nitrate on blood pressure; Dejam A, Hunter CJ, Gladwin MT.; N Engl J Med. 2006 Dec 28; 355(26):2792-3; Mother Was Right: Eat Your Vegetables and Do Not Spit!: When Oral Nitrate Helps With High Blood Pressure. David A., Wink and Nazareno Paolocci; Hypertension 2008 51 : 617-619; Acute blood pressure lowering, vasoprotective, and antiplatelet properties of dietary nitrate via bioconversion to -nitrite. Webb AJ, Patel N, Loukogeorgakis S, Okorie M, Aboud Z, Misra S, Rashid R, Miall P, Deanfield J, Benjamin N, MacAllister R, Hobbs AJ, Ahluwalia A. Hypertension 2008 Mar; 51(3):617-9; and Nitrite reduction to nitric oxide in the vasculature J. O. Lundberg and E. Weitzberg. Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H477 - H478.

DETAILED DESCRIPTION OF THE INVENTION

[069] In the following description, various aspects of the invention will be described. For the purposes of explanation, specific configurations and details are set forth in order to provide a thorough understanding of the invention. However, it will be also apparent to one skilled in the art that -the invention may be practiced without specific details presented herein. Furthermore, some well-known features may be omitted or simplified, without limiting the scope of the invention, in order not to obscure the essentials of the invention.

[070] An orally compatible, palatable composition suitable as a Nitric Oxide (NO) in vivo enhancer is provided. The palatable composition comprises an effective dosage of soluble nitrate substrate. It is a core aspect of the invention to provide the nitrate substrate in prolonged interaction with the saliva of the patient.

[071] In accordance with a further core aspect of invention, the nitrate substrate is suitable for at least partial nitrification to endothelially absorbable nitrite ions by the naturally occurring anaerobic nitrifying bacteria of the saliva of the patient. The aforementioned nitrification reduces the amount of soluble nitrate present in the patient and increases the safety and effectiveness of the palatable composition of the present invention.

[072] Nitric Oxide (NO) is an important signaling molecule which is involved in regulating a diverse range of physiological and cellular processes including the lowering of blood pressure in many tissues. In the body, NO is produced by NOS synthase enzymes L-Arginine as a substrate.

[073] The present invention provides a different pathway for NO generation, in which digested nitrate (NO₃ ^") is converted into nitric oxide and other bioactive nitrogen oxides.

[074] It has been shown that feeding patients with pills containing sodium nitrate resulted in lowering diastolic blood pressure by ca. 5%. It was further showed that the time of residence of nitrate composition in the mouth is of major importance in extracting maximum benefits from nitrate compositions.

Without wishing to be bound by theory the explanation for the above mentioned results is the following:

Nitrate anion (NO₃ ^") is a stable entity, and when introduced directly to the stomach is converted to Nitric Acid (HNO₃) without significant production of the essential molecule of interest, NO. However, upon interaction with saliva's bacteria, nitrate anions are reduced to nitrite anions which in the acidic stomach release NO, according to the following mechanism:

2NO₃- + Bacteria — ► 2NO₂- + Bacteria-O₂ 2H+ + NO₂ ^" -→ H20 + NO

The following experiments demonstrate the effect of nitrate intake on lowering blood pressure:

[075] In one experiment, healthy volunteer's blood pressure was reduced within 1 hour of ingesting beetroot juice, with a peak drop occurring 3-4 hours after ingestion. The reduction continued to be observed until up to 24 hours after ingestion. The decrease in blood pressure was shown to be due to the chemical formation of nitrite from the dietary nitrate in the juice. The nitrate in the juice is converted in saliva, by bacteria on the tongue, into nitrite.

[076] The aforementioned nitrite-containing saliva is swallowed, and in the acidic environment of the stomach is either converted into nitric oxide or re-enters the circulation as nitrite. [077] The peak time of reduction in blood pressure was shown to be correlated with the appearance and peak levels of nitrite in the circulation, an effect that was absent in a second group of volunteers who refrained from swallowing their saliva during, and for 3 hours following beetroot ingestion. This experiment demonstrates that nitrate is likely to underlie the cardioprotective effect of a vegetable-rich diet.

[078] In another experiment it was shown that swallowing beetroot juice with saliva resulted in a significant drop in blood pressure, as compared to non-saliva swallowing of the juice.

[079] The diastolic blood pressure was reduced as a result of nitrate supplementation, an effect which was correlated with peak increases in plasma nitrite concentration. In addition, plasma nitrate and nitrite levels were elevated as compared to placebo supplementation. The nitrate supplemented amount corresponds to the amount normally found in 150 to 250 g of a nitrate rich vegetable such as spinach, beetroot or lettuce.

[080] These findings provide the basis for the following core aspects of the invention:

1. Intake of nitrate source, whether from vegetable sources (beetroot) or from chemical sources (sodium nitrate) can lower blood pressure by the mechanism in which nitrate ion is reduced to nitrite ion, which subsequently produces NO in the stomach.

2. The longer the residence time of the nitrate source in the mouth, the longer the interaction of the nitrate source with anaerobic bacteria in the saliva and consequently, the more the reduction in blood pressure is effective and with lesser amounts of nitrates and nitrosating effects of nitrite and nitrate containing constituents in the patient body.

[081] The present invention provides compositions and methods for controlling vascular disorders, in which nitrate substrate is incorporated in the form of an orally compatible composition, palatable, chewable or any other preparation that have a natural long residence time in the mouth, to enable long interaction between the nitrate substrate and saliva's nitrifying bacteria.

[082] It is a core principle of the invention to provide an orally compatible, palatable composition suitable as a Nitric Oxide (NO) in vivo enhancer. The aforementioned palatable comprises an effective dosage of a soluble nitrate substrate, which is adapted for prolonged interaction with the saliva of the patient.

[083] In order to improve the interaction between the nitrate substrate and the anaerobic bacteria in the saliva, the nitrate composition of the present invention is formed in an orally compatible, palatable composition. [084] In accordance with a further core principle of the present invention, the nitrate substrate is suitable for at least partial nitrification to endothelially absorbable nitrite ions by the naturally occurring anaerobic nitrifying bacteria of the saliva.

[085] In accordance with another core principle of the present invention, the palatable composition, after reaction with the saliva, further comprises sufficient nitrite ions in a predetermined dose such that the nitrite ions are available for acidification to the nitric oxide (NO) in the stomach of the patient.

[086] In accordance with another embodiment of the invention, the prolonged interaction of the palatable composition is in the range of between about 5 sec and about 300 sec.

[087] In accordance with another embodiment of the invention, the prolonged interaction of the palatable composition is in the range of between about 300 sec and about 3000 sec.

[088] In accordance with another embodiment of the invention, the prolonged interaction of the palatable composition is in the range of between about 3000 sec and about 6 hours.

[089] In accordance with another embodiment of the invention, the substrate of the palatable composition comprises soluble nitrite ions.

[090] In accordance with another embodiment of the invention the substrate of the palatable composition comprises nitric oxide (NO).

[091] In accordance with another embodiment of the invention the nitrite ions are salts or esters of the nitrite ions.

[092] In accordance with another embodiment of the invention the composition is encapsulated by a polymeric enteric coating.

[093] In accordance with another embodiment of the invention the enteric coating is adapted for controlled release upon exposure to the oral environment.

[094] In accordance with another embodiment of the invention the enteric coating imparts protection to the composition so that the composition is protected in a low pH environment of about 3 or less while capable of releasing the composition at a pH of about 5.5 or higher.

[095] In accordance with another embodiment of the invention the polymeric coat is selected from the group consisting of polysaccharide derivatives, polyacrylic acid derivatives, polyoxyethylene derivatives and polyvinyl pyrrolidone derivatives. [096] In accordance with another embodiment of the invention the effective dosage of the palatable composition is between about 0.1 mmol and about 2 mmol per kg body weight of the patient per day.

[097] In accordance with another embodiment of the invention the effective dosage of the palatable composition is between about 2 mmol and about 100 mmol per kg body weight of the patient per day.

[098] In accordance with another embodiment of the invention the dosage of the palatable composition corresponds to the amount normally found in 150 to 250 g of the nitrate rich vegetables.

[099] In accordance with another embodiment of the invention wherein the dosage the dosage of the palatable composition corresponds to the amount normally found in 1500 to 2500 g of the nitrate rich vegetables.

[0100] In accordance with one embodiment of the present invention, the palatable composition is provided in a pretreated form, additionally comprises encapsulated anaerobic nitrifying bacteria.

[0101] In accordance with another embodiment of the present invention, the palatable composition is provided in a further pretreated form, comprises additionally to the encapsulated anaerobic nitrifying bacteria, the acidifying compounds adapted for conversion of the nitrite ions to nitric oxide (NO).

[0102] In accordance with another embodiment of the present invention the soluble nitrate substrate of the palatable composition is derived either from natural sources (fruits and vegetables) or from chemical sources (nitrate salts).

[0103] In accordance with another embodiment of the present invention, the natural source of the nitrate substrate comprises a blend of freeze-dried and/or powdered raw nitrate rich vegetables selected from a group consisting of fruiting vegetables, stem vegetables, herbs, leafy vegetables, legumes, roots and tubers or a mixture thereof. The chemical source comprises nitrate salts selected from a group consisting of sodium, potassium, lithium and calcium nitrate or a mixture thereof.

[0104] In accordance with another embodiment of the present invention, the nitrate rich vegetables further selected from a group consisting of Pumpkin, Celery, Fennel, Rhubarb, Basil, Parsley, Dill, Coriander, Chives, Borage, Amaranth, Beet, Belgian endive, Butterhead lettuce, Curled lettuce, Dandelion, Spinach, Lettuce, French beans, Beetroot, Turnip and White radish or any combination thereof.

[0105] In accordance with another embodiment of the present invention the chemical source of the nitrate substrate comprises nitrate salts selected from a group consisting of sodium, potassium, lithium and calcium nitrate or a mixture thereof.

[0106] In accordance with another embodiment of the present invention, the palatable composition is formed in a chewable form suitable for enhanced interaction of the nitrifying bacteria in the saliva. The aforementioned form is selected from a group consisting of a candy, a lozenge, a powder, a chewable tablet, tablet, a chewable gum, a chocolate bar, a lyophilized wafer, an intra-oral paper wafer, a muco-adhesive film and a non-muco-adhesive film, a tooth paste or a mouth wash.

[0107] In accordance with another embodiment of the present invention, the palatable composition additionally comprises beneficial compounds selected from a group consisting of antioxidants, trace minerals, vitamins, enzymes or any combination thereof.

[0108] In accordance with another embodiment of the present invention, the palatable composition is useful for treating vascular disorders.

[0109] In accordance with another embodiment of the present invention, the palatable composition provides an improvement in at least one of the parameters selected from a group consisting of decreased blood pressure, prevention of blood clots, protecting the lining of blood vessels, relaxing blood vessels, vasodilator therapy or any combination thereof.

[0110] In accordance with another embodiment of the present invention, the decrease in blood pressure provided by the palatable composition is characterized by an average decrease of between about 3.2 mm Hg and about 10.4 mm Hg.

[0111] In accordance with another embodiment of the present invention, the palatable composition is useful for controlling infections, especially stomach ulcers.

[0112] In accordance with another embodiment of the present invention, the palatable composition is further capable of augmenting the antimicrobial and/or antiseptic effects of stomach acid.

[0113] The present invention discloses a method of treating vascular disorders. The aforementioned method comprises steps of; (a) obtaining an orally compatible, palatable composition suitable as a Nitric Oxide (NO) in vivo enhancer; the composition comprising an effective dosage of a soluble nitrate substrate, adapted for prolonged interaction with the saliva of the patient; and, (b) administering the composition to a patient according to a predetermined protocol.

[0114] Reference is now made to the method of treating vascular disorders. The aforementioned method further comprises steps of providing an improvement in at least one of the parameters selected from a group consisting of decreased blood pressure, prevention of blood clots, protecting the lining of blood vessels, relaxing blood vessels, vasodilator therapy or any combination thereof.

[0115] Reference is now made to the method of treating vascular disorders. The aforementioned method further comprises steps of characterizing the decrease in blood pressure by an average value of between about 3.2 mm Hg and about 10.4 mm Hg.

[0116] The present invention discloses a method of treating infections, especially stomach ulcers in a patient comprising steps of; (a) obtaining an orally compatible, palatable composition suitable as a Nitric Oxide (NO) in vivo enhancer; the composition comprising an effective dosage of a soluble nitrate substrate, wherein the nitrate substrate is adapted for prolonged interaction with the saliva of the patient; and, (b) administering the composition to the patient according to a predetermined protocol.

[0117] Reference is now made to the method of treating infections. The aforementioned method is further capable of augmenting the antimicrobial and/or antiseptic effects of stomach acid.

[0118] Reference is now made to the method of treating vascular disorders and the method of treating infections. The aforementioned methods further comprise steps of adapting the nitrate substrate to be suitable for at least partial nitrification to endothelially absorbable nitrite ions by the naturally occurring anaerobic nitrifying bacteria of the saliva.

[0119] Reference is now made to the method of treating vascular disorders and the method of treating infections, wherein after reaction with the saliva, the palatable composition further comprises sufficient nitrite ions in a predetermined dose such that the ions are available for acidification to the nitric oxide (NO) in the stomach of the patient.

[0120] Reference is now made to the aforementioned methods comprising steps of obtaining the nitrate substrate adapted for prolonged interaction in a time range of between about 5 sec and about 300 sec. [0121] Reference is now made to the aforementioned methods comprising steps of obtaining the nitrate substrate adapted for prolonged interaction in a time range of between about 300 sec and about 3000 sec.

[0122] Reference is now made to the aforementioned comprising steps of obtaining the nitrate substrate adapted for prolonged interaction in a time range of between' about 3000 sec and about 6 hours.

[0123] Reference is now made to the aforementioned comprising steps of obtaining the substrate comprising soluble nitrite ions.

[0124] Reference is now made to the aforementioned methods comprising steps of obtaining the substrate adapted to comprising nitric oxide (NO).

[0125] Reference is now made to the aforementioned methods comprising steps of obtaining the nitrite ions adapted to be salts or esters of the nitrite ions.

[0126] Reference is now made to the aforementioned methods comprising steps of encapsulating-the composition by a polymeric enteric coating.

[0127] Reference is now made to the aforementioned methods comprising steps ^of adapting the enteric coating for controlled release upon exposure to the oral cavity.

[0128] Reference is now made to the aforementioned methods comprising steps of adapting the enteric coating to impart protection to the composition in the low pH environment of about 3 or less while capable of releasing the composition at a pH of about 5.5 or higher.

[0129] Reference is now made to the aforementioned methods comprising steps of selecting the polymeric coat from the group consisting of polysaccharide derivatives, polyacrylic acid derivatives, polyoxyethylene derivatives and polyvinyl pyrrolidone derivatives.

[0130] Reference is now made to the aforementioned methods comprising steps of obtaining the composition additionally comprising encapsulated anaerobic nitrifying bacteria.

[0131] Reference is now made to the aforementioned methods comprising steps of obtaining the composition additionally comprising acidifying compounds adapted for conversion of the nitrite ions to nitric oxide (NO).

[0132] Reference is now made to the aforementioned methods comprising steps of obtaining the nitrate substrate derived from a natural or chemical source. [0133] Reference is now made to the aforementioned methods comprising steps of obtaining the natural source further derived from a blend of freeze-dried and/or powdered raw nitrate rich vegetables selected from a group consisting of fruiting vegetables, stem vegetables, herbs, leafy vegetables, legumes, roots and tubers or a mixture thereof.

[0134] Reference is now made to the aforementioned methods comprising steps of selecting the nitrate rich vegetables from a group consisting of Pumpkin, Celery, Fennel, Rhubarb, Basil, Parsley, Dill, Coriander, Chives, Borage, Amarnth, Beet, Belgian endive, Butterhead lettuce, Curled lettuce, Dandelion, Spinach, Lettuce, French beans, Beetroot, Turnip and White radish or any combination thereof.

[0135] Reference is now made to the aforementioned methods comprising steps of selecting the chemical source from a group of nitrate salts consisting of sodium, potassium, lithium and calcium nitrate or a mixture thereof.

[0136] Reference is now made to the aforementioned methods comprising steps of obtaining the dosage between about 0.1 mmol and about 2 mmol per kg body weight of the patient per day.

[0137] Reference is now made to the aforementioned methods comprising steps of obtaining the dosage between about 2 mmol and about 100 mmol per kg body weight of the patient per day.

[0138] Reference is now made to the aforementioned methods comprising steps of adapting the dosage to correspond to the amount normally found in 150 to 250 g of the nitrate rich vegetables.

[0139] Reference is now made to the aforementioned methods comprising steps of adapting the dosage to correspond to the amount normally found in 1500 to 2500 g of the nitrate rich vegetables.

[0140] Reference is now made to the aforementioned methods comprising steps of obtaining the composition in the form selected from a group consisting of a candy, a lozenge, a powder, a chewable tablet, tablet, a chewable gum, a chocolate bar, a lyophilized wafer, an intra-oral paper wafer, a muco-adhesive film and a non-muco-adhesive film, a tooth paste or a mouth wash.

[0141] Reference is now made to the aforementioned methods comprising steps of obtaining the palatable composition further comprising beneficial compounds selected from a group consisting of antioxidants, trace minerals, vitamins, enzymes or any combination thereof. [0142] As used herein the term 'in vivo enhancer' refers to a composition which initiates and promotes the generation of nitric oxide (NO) from a nitrate or nitrite substrate while interacting with the saliva of the patient. The enhancer can also be, in a non limiting manner, a precursor of nitric oxide (NO).

[0143] The term 'effective dosage' used herein refers in a non-limiting manner to an amount of soluble nitrate substrate which is between about 0.1 mmol and about 2 mmol per kg body weight of the patient per day, and/ or to an amount of soluble nitrate substrate which corresponds to the amount normally found in 150 to 250 g of the detailed below nitrate rich vegetables. In some embodiments of the invention the effective dosage can be about 2 mmol mmol and about 100 mmol per kg body weight of the patient per day, and/ or to an amount of soluble nitrate substrate which corresponds to the amount normally found in 1500 to 2500 g of the detailed below nitrate rich vegetables.

[0144] The term 'prolonged interaction' used herein refers in a non-limiting manner to a time scale of between about 5 sec and about 300 sec. In other embodiments of the invention the term 'prolonged interaction¹ used herein refers in a non-limiting manner to a time scale of between about 300 sec and about 3000 sec. In other embodiments of the invention the term 'prolonged interaction' used herein refers in a non-limiting manner to a time scale of between about, bout 3000 sec and about 6 hours.

[0145] The term 'palatable composition' used hereinafter refers in a non-limiting manner to any oral composition with a relatively long interaction with mouth saliva such as candies ('pressure drops), lozenges, chewing gums, chocolate bars, tooth pastes or mouth washes.

[0146] The term 'nitrate substrate' used hereinafter refers in a non-limiting manner to any source of nitrate ions (NO₃ ^") whether derived from a natural or a chemical source.

[0147] The term 'enteric coating' used herein refers to those coatings that remain intact in the stomach, but will dissolve and release the contents of the dosage form once it reaches the small intestine. A large number of enteric coatings are prepared with ingredients that have acidic groups such that, at the very low pH present in the stomach, i.e. pH 1.5 to 2.5, the acidic groups are not ionized and the coating remains intact, in an insoluble form. At higher pH levels, such as in the environment of the intestine, the enteric coating is converted to an ionized form, which can be dissolved. Other enteric coatings remain intact until they are degraded by enzymes in the small intestine. In another embodiment of the invention the polymeric enteric coating dissolves after a defined exposure to moisture, such as the saliva, such that the coatings remain intact until after passage into the small intestine. Polymers which are useful for the preparation of enteric coatings include, but are not limited to, shellac, starch and amylose acetate phthalates, styrine-maleic acid copolymers, cellulose acetate succinate, cellulose acetate phthalate (CAP), polyvinylacetate phthalate (PVAP), hydroxypropylmethylcellulose phthalate .(grades HP-50 and HP-55), ethylcellulose, fats, butyl stearate, and methacrylic acid-methacrylic acid ester copolymers with acid ionizable groups ("EUDRAGIT™"), such as "EUDRAGIT™ L 3OD", "EUDRAGIT™ RL 3OD", "EUDRAGIT™ RS 30D", "EUDRAGIT™ L 100-55", and "EUDRAGIT™ L 30D-55". Application of the enteric coating to the palatable composition of the invention can be accomplished by any method known in the art for applying enteric coatings.

[0148] The term 'oral environment' used herein refers to the environment within the oral cavity, especially including the saliva, further including electrolytes, mucus, antibacterial compounds, and various enzymes.

[0149] The term 'nitrifying bacteria' used hereinafter refers to anaerobic bacteria in the- saliva of the patient.

[0150] The term 'nitrate rich vegetables' used hereinafter refers to any vegetable containing at least 3000 mg nitrate ions per 1 Kg of said vegetable.

[0151] The term 'freeze-dried' used hereinafter refers to conventional industrial methods of freeze drying, powdered raw preparation and dry concentrating.

[0152] The term 'beneficial compounds' used hereinafter refers to antioxidants such as iron, boron, folic acid and glutathione; vitamins such as vitamin C and vitamin E; trace minerals such as copper, manganese, chlorine, cobalt, molybdenum and zinc; and, enzymes such as catalase, superoxide dismutase, peroxidases or any combination thereof.

[0153] The term 'vascular disorders' used hereinafter refers in a non-limiting manner to decreased blood pressure, blood clots, relaxing blood vessels or any combination thereof.

[0154] In order to understand the invention and to see how it may be implemented in practice, a plurality of preferred embodiments will now be described, by way of non-limiting example only, with reference to the following examples, wherein industrial methods of preparing useful nitrate preparations are summarized: EXAMPLE 1

Nitrate preparations from vegetable and fruit juices

[0155] In order to prepare the nitric oxide enhancing palatable composition, a nitrate substrate is required. The preferably nitrate substrate used for the palatable composition of the invention is derived from a natural source, since it is safer and already includes other beneficial components. Many vegetables and fruits have considerable amounts of nitrate in either leafs, stems or roots. Some vegetables have a content of more than 3000 mg of nitrate per 1 Kg of vegetable or fruit.

[0156] The following list details nitrate rich vegetables containing at least 3000 mg of nitrate ions per 1 Kg of vegetable:

Fruiting vegetables Herbs Leafy vegetables Legumes

Pumpkin Basil Amaranth French Beans

Parsley Beet

Stem vegetables Dill Belgian endive

Coriander Butterhead lettuce Roots and Tubers

Celery Chives Curled lettuce Fennel Borage Dandelion Beetroot

Spinach Turnip Rhubarb

Lettuce White radish

[0157] A juice is extracted from a suitable vegetable. The aforementioned juice is than dry- concentrated in known industrial methods such as freeze drying to produce a safe and useful powder comprising the nitrate composition of the present invention. This useful powder additionally contains other beneficial compounds such as vitamins, trace minerals, antioxidants or any combination thereof. The aforementioned powder is then incorporated in predetermined amounts, in known industrial methods, into any of the above mentioned palatable preparations such as candies, lozenges, chewing gums or tooth pastes in order to increase the time and surface interaction with saliva's bacteria of a patient. EXAMPLE 2

Nitrate preparations from chemical nitrate salts An alternative method of preparing the nitric oxide enhancing palatable composition of the invention is by using a nitrate substrate derived from a chemical source. The aforementioned palatable composition is prepared by mixing a predetermined amount of nitrate salts such as sodium, potassium, lithium or calcium nitrate with other beneficial compounds such as vitamins, trace minerals, antioxidants or any combination thereof to incorporate them in predetermined amounts into the above mentioned palatable preparations.

Claims

1. An orally compatible, palatable composition suitable as a Nitric Oxide (NO) in vivo enhancer; said composition comprising an effective dosage of a soluble nitrate substrate, wherein said nitrate substrate is adapted for prolonged interaction with the saliva of the patient, further wherein said nitrate substrate is suitable for at least partial nitrification to endothelially absorbable nitrite ions by the naturally occurring anaerobic nitrifying bacteria of said saliva.

2. The palatable composition according to claim 1, wherein said composition, after reaction with said saliva, further comprises sufficient nitrite ions in a predetermined dose such that said ions are available for acidification to said nitric oxide (NO) in the stomach of said patient.

3. The palatable composition according to claim 1, wherein said prolonged interaction is in the range of between about 5 sec and about 300 sec.

4. The palatable composition according to claim 1, wherein said prolonged interaction is in the range of between about 300 sec and about 3000 sec.

5. The palatable composition according to claim 1, wherein said prolonged interaction is in the range of between about 3000 sec and about 6 hours.

6. The palatable composition according to claim 1, wherein said substrate comprises soluble nitrite ions.

7. The palatable composition according to claim 1, wherein said substrate comprises nitric oxide (NO).

8. The palatable composition according to claim 6, wherein said nitrite ions are salts or esters of said nitrite ions.

9. The palatable composition according to claim 1, wherein said composition is encapsulated by a polymeric enteric coating.

10. The palatable composition according to claim 9, wherein said enteric coating is adapted for controlled release upon exposure to the oral environment.

11. The palatable composition according to claim 9, wherein said enteric coating imparts protection to said composition so that said composition is protected in a low pH environment of about 3 or less while capable of releasing said composition at a pH of about 5.5 or higher.

12. The palatable composition according to claim 9, wherein said polymeric coat is selected from the group consisting of polysaccharide derivatives, polyacrylic acid derivatives, polyoxyethylene derivatives and polyvinyl pyfrolidone derivatives.

13. The palatable composition according to claim 1, wherein said composition additionally comprises encapsulated anaerobic nitrifying bacteria.

14. The palatable composition according to claim 13, wherein said composition additionally comprises acidifying compounds adapted for conversion of said nitrite ions to nitric oxide (NO).

15. The palatable composition according to claim 1, wherein said nitrate substrate is derived from a natural or chemical source.

16. The palatable composition according to claim 15, wherein said natural source comprises a blend of freeze-dried and/or powdered raw nitrate rich vegetables selected from a group consisting of fruiting vegetables, stem vegetables, herbs, leafy vegetables, legumes, roots and tubers or a mixture thereof.

17. The palatable composition according to claim 16, wherein said nitrate rich vegetables are further selected from a group consisting of Pumpkin, Celery, Fennel, Rhubarb, Basil, Parsley, Dill, Coriander, Chives, Borage, Amarinth, Beet, Belgian endive, Butterhead lettuce, Curled lettuce, Dandelion, Spinach, Lettuce, French beans, Beetroot, Turnip and White radish or any combination thereof.

18. The palatable composition according to claim 15, wherein said chemical source comprises nitrate salts selected from a group consisting of sodium, potassium, lithium and calcium nitrate or a mixture thereof.

19. The palatable composition according to claim 1, wherein said dosage is between about 0.1 mmol and about 2 mmol per kg body weight of said patient per day.

20. The palatable composition according to claim 1, wherein said dosage is between about 2 mmol and about 100 mmol per kg body weight of said patient per day.

21. The palatable composition according to claim 1, wherein said dosage corresponds to the amount normally found in 150 to 250 g of said nitrate rich vegetables.

22. The palatable composition according to claim 1, wherein said dosage corresponds to the amount normally found in 1500 to 2500 g of said nitrate rich vegetables.

23. The palatable composition according to claim 1, wherein said composition is in a form selected from a group consisting of a candy, a lozenge, a powder, pellets, a chewable tablet, tablet, a chewable gum, a chocolate bar, a lyophilized wafer, an intra-oral paper wafer, a muco-adhesive film and a non-muco-adhesive film, a tooth paste or a mouth wash.

24. The palatable composition according to claim 1, wherein said palatable composition additionally comprises beneficial compounds selected from a group consisting of antioxidants, trace minerals, vitamins, enzymes or any combination thereof.

25. The palatable composition according to claim 1, wherein said composition is useful for treating vascular disorders.

26. The palatable composition according to claim 25, wherein said composition provides an improvement in at least one of the parameters selected from a group consisting of decreased blood pressure, prevention of blood clots, protecting the lining of blood vessels, relaxing blood vessels, vasodilator therapy or any combination thereof.

27. The palatable composition according to claim 26, wherein said decreased blood pressure is characterized by an average decrease of between about 3.2 mm Hg and about 10.4 mm Hg.

28. The palatable composition according to claim 1, wherein said composition is useful for controlling infections, especially stomach ulcers.

29. The palatable composition according to claim 28, wherein said composition is further capable of augmenting the antimicrobial and/or antiseptic effects of stomach acid.

30. A method of treating vascular disorders, said method comprises steps of; a. obtaining an orally compatible, palatable composition suitable as a Nitric Oxide (NO) in vivo enhancer; wherein said composition comprises an effective dosage of a soluble nitrate substrate adapted for prolonged interaction with the saliva of the patient; further wherein said nitrate substrate is suitable for at least partial nitrification to endothelially absorbable nitrite ions by the naturally occurring anaerobic nitrifying bacteria of said saliva; and, b. administering said composition to said patient according to a predetermined protocol.

31. The method according to claim 30, wherein said method comprises steps of providing an improvement in at least one of the parameters selected from a group consisting of decreased blood pressure, prevention of blood clots, protecting the lining of blood vessels, relaxing blood vessels, vasodilator therapy or any combination thereof.

32. The method according to claim 31, wherein said method comprises steps of characterizing said decrease in blood pressure by an average decrease of between about 3.2 mm Hg and about 10.4 mm Hg.

33. A method of treating infections, especially stomach ulcers in a patient comprising steps of; a. obtaining an orally compatible, palatable composition suitable as a Nitric Oxide (NO) in vivo enhancer; wherein said composition comprises an effective dosage of a soluble nitrate substrate adapted for prolonged interaction with the saliva of the patient; and, further wherein said nitrate substrate is suitable for at least partial nitrification to endothelially absorbable nitrite ions by the naturally occurring anaerobic nitrifying bacteria of said saliva; and, b. administering said composition to said patient according to a predetermined protocol.

34. The method according to claim 33, wherein said method further comprises steps of augmenting the antimicrobial and/or antiseptic effects of stomach acid.

35. The method according to any of claims 30 and 33, wherein said method comprises steps of obtaining said composition adapted to comprise sufficient nitrite ions, after reaction with said saliva, in a predetermined dose such that said ions are available for acidification to said nitric oxide (NO) in the stomach of said patient.

36. The method according to any of claims 30 and 33, wherein said method comprises steps of obtaining said nitrate substrate adapted for prolonged interaction in a time range of between about 5 sec and about 300 sec.

37. The method according to any of claims 30 and 33, wherein said method comprises steps of obtaining said nitrate substrate adapted for prolonged interaction in a time range of between about 300 sec and about 3000 sec.

38. The method according to any of claims 30 and 33, wherein said method comprises steps of obtaining^" said nitrate substrate adapted for prolonged interaction in a time range of between about 3000 sec and about 6 hours.

39. The method according to any of claims 30 and 33, wherein said method comprises steps of obtaining said substrate adapted to comprise soluble nitrite ions.

40. The method according to any of claims 30 and 33, wherein said method comprises steps of obtaining said substrate adapted to comprise nitric oxide (NO).

41. The method according to any of claims 30 and 33, wherein said method comprises steps of obtaining said nitrite ions adapted to be salts or esters of said nitrite ions.

42. The method according to any of claims 30 and 33, wherein said method comprises steps of encapsulating said composition by a polymeric enteric coating.

43. The method according to claim 42, wherein said method comprises steps of adapting said enteric coating for controlled release upon exposure to the oral environment.

44. The method according to claim-42, wherein said method comprises steps of adapting said enteric coating to impart protection to said composition in the low pH environment of about 3 or less while capable of releasing said composition at a pH of about 5.5 or higher.

45. The method according to claim 42, wherein said method comprises steps of selecting said polymeric coat from the group consisting of polysaccharide derivatives, polyacrylic acid derivatives, polyoxyethylene derivatives and polyvinyl pyrrolidone derivatives.

46. The method according to any of claims 30 and 33, wherein said method comprises steps of obtaining said composition additionally comprising encapsulated anaerobic nitrifying bacteria.

47. The method according to claim 46, wherein said method comprises steps of obtaining said composition additionally comprising acidifying compounds adapted for conversion of said nitrite ions to nitric oxide (NO).

48. The method according to any of claims 30 and 33, wherein said method comprises steps of obtaining said nitrate substrate derived from a natural or chemical source.

49. The method according to claim 48, wherein said method comprises steps of obtaining said natural source further derived from a blend of freeze-dried and/or powdered raw nitrate rich vegetables selected from a group consisting of fruiting vegetables, stem vegetables, herbs, leafy vegetables, legumes, roots and tubers or a mixture thereof.

50. The method according to claim 49, wherein said method comprises steps of selecting said nitrate rich vegetables from a group consisting of Pumpkin, Celery, Fennel, Rhubarb, Basil, Parsley, Dill, Coriander, Chives, Borage, Amarnth, Beet, Belgian endive, Butterhead lettuce, Curled lettuce, Dandelion, Spinach, Lettuce, French beans, Beetroot, Turnip and White radish or any combination thereof.

51. The method according to claim 48, wherein said method comprises steps of selecting said chemical source from a group of nitrate salts consisting of sodium, potassium, lithium and calcium nitrate or a mixture thereof.

52. The method according to any of claims 30 and 33, wherein said method comprises steps of obtaining said dosage between about 0.1 mmol and about 2 mmol per kg body weight of said patient per day.

53. The method according to any of claims 30 and 33, wherein said method comprises steps of obtaining said dosage between about 2 mmol and about 100 mmol per kg body weight of said patient per day.

54. The method according to any of claims 30 and 33, wherein said method comprises steps of adapting said dosage to correspond to the amount normally found in 150 to 250 g of said nitrate rich vegetables.

55. The method according to any of claims 30 and 33, wherein said method comprises steps of adapting said dosage to correspond to the amount normally found in 1500 to 2500 g of said nitrate rich vegetables.

56. The method according to any of claims 30 and 33, wherein said method comprises steps of obtaining said composition in the form selected from a group consisting of a candy, a lozenge, a powder, a chewable tablet, tablet, a chewable gum, a chocolate bar, a lyophilized wafer, an intra-oral paper wafer, a muco-adhesive film and a non-muco- adhesive film, a tooth paste or a mouth wash.

7. The method according to any of claims 30 and 33, wherein said method comprises steps of obtaining said palatable composition further comprising beneficial compounds selected from a group consisting of antioxidants, trace minerals, vitamins, enzymes or any combination thereof.